This project investigates the role of NKX3.1 in protection against DNA damage in the prostate epithelium, which may provide a key mechanism for its function in tumor suppression, NKX3.I is a prostate specific homeobox gene located on 8p21, the target for the most frequent chromosomal loss in human prostate cancer. NKX3.I is also a tumor suppressor for which reduced protein expression is sufficient to deregulate prostate epithelial cell growth and cause Intraepithelial neoplasia;moreover, Nkx3.1 haploinsufficiency results in prostate epithelial dysplasia in mice. Consistent with its role as a tumor suppressor in human prostate cancer, we have shown that an Inactivating mutation In the NKX3.I homeodomain cosegregates with early onset prostate cancer in a prostate cancer family. In recent studies, we have shown that NKX3.1 enhances cell survival after DNA damage and affects the earliest events in recognition of DNA breaks, including formation of YH2AX foci and phosphorylation of ATM. Based on our hypothesis that a key mechanism by which NKX3.1 loss contributes to tumor initiation is through its impact on the DNA damage response, our studies will define the mechanistic role of NKX3.I in the DNA damage response in vitro, as well as its impact on DNA damage in vivo. We also will determine whether NKX3.I mediates the susceptibility of prostate cells to formation of the characteristic TMPRSS2- ERG chromosomal rearrangement that occurs in approximately 50% of prostate cancers. Taken together, our three aims will delineate the role of NKXS.I in the DNA damage response in distinct contexts, thereby providing a comprehensive investigation of this key mechanism of tumor suppression.
In Aim 1, our experiments will define the dynamics of the functional interaction between NKX3.1 and ATM, which occurs within minutes of DNA damage.
In Aim 2, we will determine whether Nkx3.I gene copy number affects the DNA damage response in vivo in the prostate epithelium, and particularly in prostate epithelial stem cells. Finally, in Aim 3, using unique lines of LNCaP cells that we have derived, we will determine whether NKX3.1 affects the frequency of TMPRSS2-ERG gene rearrangements. These proposed studies will be highly integrated with the overall program project. Notably, the experiments in Aim 2 include quantitative immunostaining analyses in collaboration with Core A, the work in Aim 2 on the prostate stem cells will be performed in collaboration with Michael Shen (Project 1), and the entirety of this project is linked to the molecular analyses of Nkx3.1 in cellular senescence by Cory Abate-Shen (Project 2).

Public Health Relevance

Prostate cancer is diagnosed in nearly 200,000 men a year and is responsible for 29,000 deaths annually. Our lab has been the lead proponent of a central role of NKX3.I loss in the earliest stages of prostate cancer initiation. The current project will elucidate a key mechanism of NKX3.1 tumor suppression, namely protection against DNA damage. Our long term goal is to identify mechanisms that will lead to upregulation of NKX3.1 as a strategy for prostate cancer prevention or treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
New York
United States
Zip Code
Chen, James C; Alvarez, Mariano J; Talos, Flaminia et al. (2014) Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell 159:402-14
Aytes, Alvaro; Mitrofanova, Antonina; Lefebvre, Celine et al. (2014) Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25:638-51
Wang, Zhu A; Toivanen, Roxanne; Bergren, Sarah K et al. (2014) Luminal cells are favored as the cell of origin for prostate cancer. Cell Rep 8:1339-46
Chua, Chee Wai; Shibata, Maho; Lei, Ming et al. (2014) Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol 16:951-61, 1-4
Bowen, Cai; Ju, Jeong-Ho; Lee, Ji-Hoon et al. (2013) Functional activation of ATM by the prostate cancer suppressor NKX3.1. Cell Rep 4:516-29
Irshad, Shazia; Bansal, Mukesh; Castillo-Martin, Mireia et al. (2013) A molecular signature predictive of indolent prostate cancer. Sci Transl Med 5:202ra122
Aytes, Alvaro; Mitrofanova, Antonina; Kinkade, Carolyn Waugh et al. (2013) ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proc Natl Acad Sci U S A 110:E3506-15
Jin, Feng; Irshad, Shazia; Yu, Wei et al. (2013) ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity. Mol Cancer Res 11:736-47
Wang, Zhu A; Mitrofanova, Antonina; Bergren, Sarah K et al. (2013) Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 15:274-83
Shen, Michael M (2013) Chromoplexy: a new category of complex rearrangements in the cancer genome. Cancer Cell 23:567-9

Showing the most recent 10 out of 11 publications